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Updated: May 31, 2026
08:48
Development of a Backbone Cyclic Peptide Library as Potential Antiparasitic Therapeutics Using Microwave Irradiation
Published on: January 26, 2016
Evolution of cyclic peptide protease inhibitors
Travis S Young1, Douglas D Young, Insha Ahmad
1Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Summary
Researchers engineered a bacterial system using novel amino acids to evolve cyclic peptides. This approach successfully generated a potent HIV protease inhibitor, demonstrating the evolutionary advantage of an expanded genetic code.
Area of Science:
- Biochemistry
- Molecular Biology
- Synthetic Biology
Background:
- Ribosomal peptide synthesis typically uses a standard set of 20 amino acids.
- Expanding the repertoire of amino acids can lead to novel peptide structures and functions.
- Bacterial systems offer a powerful platform for peptide evolution and drug discovery.
Purpose of the Study:
- To develop a bacterial system for evolving cyclic peptides using an expanded genetic code.
- To generate a library of peptides with unique amino acid building blocks.
- To evolve a potent inhibitor of HIV protease.
Main Methods:
- Utilized orthogonal aminoacyl-tRNA synthetase/tRNA(CUA) pairs and a split intein system for peptide biosynthesis.
- Created a peptide library incorporating non-canonical amino acids.
- Employed a cell viability-based selection to evolve HIV protease inhibitors.
Main Results:
- Successfully biosynthesized a library of ribosomal peptides with unique amino acid structures.
- Isolated cyclic peptides that inhibited HIV protease after two rounds of selection.
- Identified a potent inhibitor containing p-benzoylphenylalanine (pBzF) that forms a covalent adduct with HIV protease.
Conclusions:
- An expanded genetic code provides an evolutionary advantage under selective pressure.
- Combining natural evolution with chemically biased building blocks enables microbial generation of bioactive peptides.
- This strategy offers a novel approach for developing peptide-based therapeutics.
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